Recently, dementia patients associated with Alzheimer's disease have been increasing with the growing number of the elderly population. Anticholinesterase agents such as donepezil hydrochloride and rivastigmine tartrate have been developed as anti-dementia drugs for Alzheimer's disease. These agents have been prescribed for dementia patients as oral preparations such as tablets and liquids in clinical practice.
However, dementia patients often have difficulty in taking therapeutic agents by themselves because advanced dementia causes poor medication compliance or decreased swallowing function. Accordingly, development of transdermal agents has been needed which can solve these problems to achieve stable administration of therapeutic agents.
Now, transdermal agents are being developed using rivastigmine as one of anti-dementia drugs for Alzheimer's disease. However, lotions prepared using rivastigmine increased the skin permeability of the drug just after administration but had difficulty in keeping continuous cutaneous absorption of the drug in an amount sufficient to obtain a desired drug effect for one day or longer. In addition, adhesive patches prepared using rivastigmine had difficulty in stably containing a high concentration of rivastigmine, which is liquid at room temperature, in a medicated layer. For this reason, it is difficult for adhesive patches to increase the skin permeation of rivastigmine to such an extent that a desired drug effect is obtained. In order to solve these problems, various studies have been made on adhesive patches containing rivastigmine.
Patent Literature 1 describes an adhesive patch which includes in combination rivastigmine tartrate, an acrylic adhesive (such as alkyl amino methacrylate copolymer), an acrylic acid polymer, and a surfactant. However, there is no description of the storage stability of rivastigmine tartrate in the adhesive patch and the skin permeability of rivastigmine in Patent Literature 1.
Patent Literature 2 describes an adhesive patch which includes in combination rivastigmine, polymethacrylate, an acrylate copolymer containing a carboxy group, and an antioxidant. Patent Literature 2 describes that the antioxidant was used for suppressing decomposition of rivastigmine in the adhesive patch and the antioxidant improved the storage stability of rivastigmine. However, there is no description of the skin permeability of rivastigmine in the adhesive patch in Patent Literature 2.
Patent Literature 3 describes an adhesive patch with a two-layer structure composed of, in combination, a storage layer comprising rivastigmine, a polyacrylate adhesive containing a carboxy group, an acrylate copolymer, and vitamin E; and a silicone adhesive layer comprising a silicone adhesive, a silicone oil, and vitamin E. Patent Literature 3 describes that such an adhesive patch has excellent adhesion to the skin and skin permeability. However, the storage layer and the adhesive layer are laid on each other after these two layers are separately produced, requiring a complex process for producing the adhesive patch in Patent Literature 3. In addition, rivastigmine, vitamin E used as an antioxidant, and other components move between the storage layer and the adhesive layer during the storage of the adhesive patch, so that the skin permeability of rivastigmine in the adhesive patch may change depending on the storage period of the adhesive patch.
Patent Literature 4 discloses an adhesive patch which includes in combination rivastigmine, an acrylic adhesive without containing any cross-linking agent containing a metal atom, and a volatilization inhibitor such as squalane and triethyl citrate. Pressure-sensitive acrylic polymers having a carboxy group in a side chain were disclosed as examples of suitable acrylic adhesives in the patent literature 4. The volatilization inhibitor is used for suppressing loss of rivastigmine due to volatilization of rivastigmine during the production, which rivastigmine is liquid at room temperature. Patent Literature 4 discloses the study on improvement in the adhesion of the adhesive patch but has no description on the storage stability of rivastigmine.